Interactions between dopaminergic and cannabinoid receptors in the basal ganglia have only recently been elucidated. The basal ganglia regulate movement, and when there is substantial cell death in centers in the basal ganglia, profound motor dysfunction can result. Of great importance is the neurodegenrative Parkinson's disease, in which a majority of the dopamine-containing neurons in the substantia nigra pars compacta in the basal ganglia have degenerated. Although research on Parkinson's disease has been dominated by investigations of the role of dopamine in basal ganglia nuclei, current researchers and clinicians are implicating roles for other receptor systems in these nuclei. Therapy for this disease primarily involves drugs that enhance dopaminergic transmission; however, clinicians have also used other classes of drugs to alleviate symptoms in these patients. These other classes of drugs work on different receptor systems and may enhance dopamine release. This research proposal involves an investigation of a nondopaminergic drug and its potential effects on alleviating the symptoms of Parkinson's disease. Because cannabinoid agonists cause a rigid immobility in rats mimicking Parkinson's disease, a cannabinoid antagonist might alleviate some of the symptoms of this disease. Recent evidence suggests that a cannabinoid antagonist might enhance dopamine transmission and antagonize cholinergic activity in the basal ganglia. Thus, a cannabinoid antagonist may cause a positive therapeutic effect in Parkinson's patients. To test this, a dopaminergically compromised rat and a primate MPTP model of early stage Parkinson's disease will be used to determine the therapeutic potential of a cannabinoid antagonist. In addition to behavioral studies in whole animals, the biochemical interactions between cannabinoid and dopamine receptors in these nuclei will be investigated. Using dissected rat and primate basal ganglial nuclei, receptor co-localization and signal transduction convergence will be elucidated. Adenylate cyclase and [35S] GTP-gamma-S binding assays will be used to determine maximum activity, drug-drug additivity and interactions between one receptor system and another. With these studies, dopamine and cannabinoid interactions will be elucidated and the potential for a new class of therapeutic agents for Parkinson's disease will be determined.